VCV002860762.2 - ClinVar

NM_000487.6(ARSA):c.1288C>T (p.Leu430Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000487.6(ARSA):c.1288C>T (p.Leu430Phe)

Variation ID: 2860762 Accession: VCV002860762.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50625387 (GRCh38) [ NCBI UCSC ] 22: 51063815 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2024	Jun 2, 2024	Aug 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.1288C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000478.3:p.Leu430Phe	missense
NM_000487.5:c.1288C>T
NM_001085425.3:c.1288C>T	NP_001078894.2:p.Leu430Phe	missense
NM_001085426.3:c.1288C>T	NP_001078895.2:p.Leu430Phe	missense
NM_001085427.3:c.1288C>T	NP_001078896.2:p.Leu430Phe	missense
NM_001085428.3:c.1030C>T	NP_001078897.1:p.Leu344Phe	missense
NM_001362782.2:c.1030C>T	NP_001349711.1:p.Leu344Phe	missense
NC_000022.11:g.50625387G>A
NC_000022.10:g.51063815G>A
NG_009260.2:g.7793C>T

... more HGVS ... less HGVS

Protein change

L430F, L344F

Other names

Canonical SPDI

NC_000022.11:50625386:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

functionally_normal; Sequence Ontology [ SO:0002219]

As described in PMID: 37480112, ARSA enzymatic activity >13% of wild type is taken as benign and likely does not contribute to disease. [submitted by Gelb Laboratory, University of Washington]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ARSA		-	-	GRCh38 GRCh37	1256	1424

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Metachromatic leukodystrophy	Likely pathogenic (2)	criteria provided, single submitter	Aug 4, 2023	RCV003608382.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Aug 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004461817.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 9272717‚ 26462614 Comment: This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 430 of the ARSA protein (p.Leu430Phe). … (more) This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 430 of the ARSA protein (p.Leu430Phe). This variant is present in population databases (rs763190974, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. This variant disrupts the p.Leu430 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9272717, 26462614; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
not provided (-)	no classification provided Method: in vitro	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: not applicable Allele origin: not applicable	Gelb Laboratory, University of Washington Accession: SCV005046744.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Publications: PubMed (1) PubMed: 37480112 Comment on evidence: 0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken … (more) 0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken as mild, and >13% is taken as benign, see PMID: 37480112 (less) Method: tandem mass spectrometry used to measure enymatic activity Result: 62% of wild type enzymatic activity

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 430 of the ARSA protein (p.Leu430Phe). This variant is present in population databases (rs763190974, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. This variant disrupts the p.Leu430 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9272717, 26462614; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
functionally_normal (SO:0002219)	tandem mass spectrometry used to measure enymatic activity Method citation(s): PubMed(1)	62% of wild type enzymatic activity	Gelb Laboratory, University of Washington Accession: SCV005046744.1	Publications PubMed (1) Comment: As described in PMID: 37480112, ARSA enzymatic activity >13% of wild type is taken as benign and likely does not contribute to disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.	Trinidad M	Genome biology	2023	PMID: 37480112
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.	Cesani M	Human mutation	2016	PMID: 26462614
A T > C transition causing a Leu > Pro substitution in a conserved region of the arylsulfatase A gene in a late infantile metachromatic leukodystrophy patient.	Regis S	Clinical genetics	1997	PMID: 9272717

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000487.6(ARSA):c.1288C>T (p.Leu430Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...